sST2 translation is regulated by FGF2 via an hnRNP A1-mediated IRES-dependent mechanism

Biochim Biophys Acta. 2016 Jul;1859(7):848-59. doi: 10.1016/j.bbagrm.2016.05.005. Epub 2016 May 8.

Abstract

Translation is an energy-intensive process and tightly regulated. Generally, translation is initiated in a cap-dependent manner. Under stress conditions, typically found within the tumor microenvironment in association with e.g. nutrient deprivation or hypoxia, cap-dependent translation decreases, and alternative modes of translation initiation become more important. Specifically, internal ribosome entry sites (IRES) facilitate translation of specific mRNAs under otherwise translation-inhibitory conditions. This mechanism is controlled by IRES trans-acting factors (ITAF), i.e. by RNA-binding proteins, which interact with and determine the activity of selected IRESs. We aimed at characterizing the translational regulation of the IL-33 decoy receptor sST2, which was enhanced by fibroblast growth factor 2 (FGF2). We identified and verified an IRES within the 5'UTR of sST2. Furthermore, we found that MEK/ERK signaling contributes to FGF2-induced, sST2-IRES activation and translation. Determination of the sST2-5'UTR structure by in-line probing followed by deletion analyses identified 23 nucleotides within the sST2-5'UTR to be required for optimal IRES activity. Finally, we show that the RNA-binding protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds to the sST2-5'UTR, acts as an ITAF, and thus controls the activity of the sST2-IRES and consequently sST2 translation. Specifically, FGF2 enhances nuclear-cytoplasmic translocation of hnRNP A1, which requires intact MEK/ERK activity. In summary, we provide evidence that the sST2-5'UTR contains an IRES element, which is activated by a MEK/ERK-dependent increase in cytoplasmic localization of hnRNP A1 in response to FGF2, enhancing the translation of sST2.

Keywords: IRES; ITAF; MEK/ERK; RNA-binding protein; hnRNP A1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / drug effects
  • Binding Sites / drug effects
  • Fibroblast Growth Factor 2 / pharmacology*
  • Gene Expression Regulation / drug effects
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / physiology*
  • Humans
  • Interleukin-1 Receptor-Like 1 Protein
  • Internal Ribosome Entry Sites / physiology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • MCF-7 Cells
  • Protein Biosynthesis* / drug effects
  • Protein Biosynthesis* / genetics
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism*
  • Solubility

Substances

  • 5' Untranslated Regions
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • IL1RL1 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Internal Ribosome Entry Sites
  • Receptors, Cell Surface
  • Fibroblast Growth Factor 2